Department of Neurobiology, Graduate School of medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
Sci Rep. 2018 Jan 26;8(1):1692. doi: 10.1038/s41598-018-20090-0.
Disc1 is a susceptibility gene for psychiatric disorders including schizophrenia. It has been suggested that excess transmission through dopamine type 2 receptors (D2Rs) in the striatum is an underlying mechanism of pathogenesis. In this study, we used super-resolution microscopy to study the distribution of D2Rs at the nanoscale in mice lacking exons 2 and 3 of Disc1 (Disc1-deficient mice). We found that D2Rs in the nucleus accumbens (NAc) of wild-type mice form nanoclusters (~ 20,000 nm), and that Disc1-deficient mice have larger and more D2R nanoclusters than wild-type mice. Interestingly, administration of clozapine reduced the size and spatial distribution of the nanoclusters only in Disc1-deficient mice. Moreover, we observed that medium spiny neurons in the NAc of Disc1-deficient mice had reduced spine density on their dendrites than did wild-type mice, and this was also reversed by clozapine administration. The altered D2R nanoclusters might be morphological representations of the altered dopaminergic transmission in disease states such as schizophrenia.
Disc1 是包括精神分裂症在内的精神障碍的易感基因。有人提出，纹状体中多巴胺 D2 受体（D2Rs）的过度传递是发病机制的潜在机制。在这项研究中，我们使用超分辨率显微镜研究了缺失 Disc1 外显子 2 和 3 的小鼠（Disc1 缺陷型小鼠）中纹状体中 D2Rs 的纳米尺度分布。我们发现，野生型小鼠伏隔核（NAc）中的 D2Rs 形成纳米簇（~20000nm），而 Disc1 缺陷型小鼠的 D2R 纳米簇比野生型小鼠更大且更多。有趣的是，氯氮平仅在 Disc1 缺陷型小鼠中减少了纳米簇的大小和空间分布。此外，我们观察到，Disc1 缺陷型小鼠 NAc 中的中间棘神经元的树突上的棘密度比野生型小鼠减少，氯氮平的给药也逆转了这种情况。改变的 D2R 纳米簇可能是疾病状态（如精神分裂症）中改变的多巴胺能传递的形态代表。
